Findings
In this decision analytic modeling study based on clinical trial data, neither aducanumab nor donanemab was cost-effective at their expected prices of more than $25 000/y. Aducanumab became cost-effective when priced below $3000/y, whereas owing to its possibly greater efficacy (based on phase 2 trial data) and limited-duration dosing, donanemab was cost-effective when priced around $20 000/y. Value-based price estimates for aducanumab and donanemab, in 2020 US dollars, are shown at varying values of treatment efficacy expressed in terms of disease progression hazard ratio (HR) relative to placebo. Solid lines show value-based price estimates for aducanumab and donanemab using base-case inputs (except for efficacy); shaded areas indicate 95% CIs derived from probabilistic sensitivity analysis around all parameters except efficacy. Diamonds indicate the value-based prices of aducanumab and donanemab at their base-case efficacy values. Until recently, all approved treatments for AD were symptomatic and not disease modifying.
- The company attributed that figure partly to drug wholesalers drawing down inventory they had purchased the previous quarter.
- The drugmaker said Monday that it will cut the wholesale acquisition cost of the drug by about 50% next month.
- At the upper bound of cost ($84,000) the ICER was $622,000/QALY and at the lower bound of cost ($33,600) it was $191,940/QALY.
- After months of concern raised by the Alzheimer disease community about the list price for aducanumab (Aduhelm) of $56,000 yearly, Biogen has announced that the maintenance dose cost will be reduced to $28,200.
- In the studies, individuals who were ApoE ɛ4 carriers and ApoE ɛ4 non-carriers were enrolled.
- We found that an indefinitely dosed treatment would not warrant a price of greater than $50 000/y, as was initially proposed for aducanumab, even if it slowed disease progression by 90%.
Additionally, the delayed start design with termination for futility did not help with the completeness or interpretability of long-term follow-up data in these studies. Our findings suggest that at their current expected prices, neither aducanumab nor donanemab would be cost-effective for the treatment of early AD in the US. Although aducanumab’s price would need to fall to less than $3000/y to become cost-effective, donanemab—if its efficacy is confirmed in phase 3 trials—could be cost-effective when priced at $20 000/y. The limited-duration dosing scheme used with donanemab is critical to its greater health-economic value; this approach may provide a rubric by which sufficiently effective anti-amyloid drugs could be economically viable in the US health care system, even when priced comparably to other biologics. Knopman et al. published a critical review of the two aducanumab trials.16 The authors state that although it is possible that aducanumab has cognitive benefits, the available data are insufficient to make a “claim of efficacy” for the drug. They state that even after considering the issues caused by the termination of these trials prematurely, having only one positive trial with the other trial being negative means that the evidence regarding the drug’s efficacy is not conclusive.
The cost‐effectiveness acceptability curve shows that aducanumab was favored 0.76% of the time at the WTP threshold of 100,000/QALY (Figure S3 in supporting information). “We believe that both the federal government and the states deserve better policy options in the face of a historic drug approval. Protecting state budgets shouldn’t require Medicare to cover an expensive drug with unproven clinical benefits, and Congress should take steps to fix this problem. Perhaps aducanumab’s high price will finally provide the impetus for revisiting Medicare’s and Medicaid’s existing commitments to covering all FDA-approved drugs,” Sachs and Bagley concluded. We conducted one‐way deterministic sensitivity analyses using a priori feasible ranges around core parameter values. We conducted a threshold analysis of aducanumab costs to assess the cost at which the drug would meet our WTP threshold.
Controversy: Insufficient data to support efficacy
We developed a Markov state transition model of AD to estimate the cost effectiveness of aducanumab compared to standard of care (SOC) over a 5‐year time horizon for a cohort of persons aged 65 with mild AD. Outcomes included quality adjusted life years (QALYs), discounted costs, and incremental cost‐effectiveness ratios (ICERs). The provision of care would be constrained by the limited capacity of dementia specialists to evaluate and diagnose patients and by limited access to imaging sites to confirm the diagnosis of AD and infusion centres to deliver the treatment.
We developed a Markov state‐transition model of AD to project the incremental cost‐effectiveness ratio (ICER) of aducanumab compared to standard of care (SOC) over a 5‐year time horizon for a cohort of persons aged 65 years with mild AD. The model simulates the progression of patients with mild AD to moderate and, subsequently, severe AD (Figure S1 in supporting information). Each AD disease state carries distinct costs, disability weights, and mortality rates. We projected lifetime medical costs assuming a health‐care system perspective and applied a 3% discount rate to costs and quality‐adjusted life years (QALYs). 4
We interpreted ICERs using a willingness‐to‐pay (WTP) threshold of $100,000/QALY gained. We found that an indefinitely dosed treatment would not warrant a price of greater than $50 000/y, as was initially proposed for aducanumab, even if it slowed disease progression by 90%.
The approval will bring massive financial gains for Biogen, which saw its shares gain 38 per cent after the nod to its drug. The company has said that it would charge an average of $56,000 a year per patient to use the drug which is going to be one of the best-selling pharmaceutical products in the world. Alzheimer’s disease is the most common form of dementia and contributes per cent of the cases. According to the World Health Organisation (WHO), it is a syndrome in which there is deterioration in memory, thinking, behaviour and the ability to perform everyday activities. The agency said about half of that hike was due to the need for a contingency fund to cover Aduhelm.
On 7 June 2021, the US FDA approved aducanumab, a human IgG1 anti-Aβ monoclonal antibody selective for Aβ aggregates, as the first disease-modifying treatment for AD. Aducanumab is approved in the United States for the treatment of mild cognitive impairment or mild-dementia stage of AD. In this Editorial, we review the trial data for aducanumab in the treatment of AD and the controversies that its approval has generated.
Alzheimer’s dementia is the most common type and involves plaques and tangles forming in the brain. Forgetfulness and memory problems are often early symptoms, but as the illness progresses, patients tend to become confused, may lose their way around familiar places, and have difficulties with planning and completing simple tasks. Dr Rajas Deshpande, neurologist at Lilavati Hospital, Mumbai, said the disease is basically an accelerated ageing of certain neurons in the brain that are concerned with storage and processing of memory. A new drug for treatment of Alzheimer’s disease holds promise, but comes with several caveats.
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Some states, such as Massachusetts and Tennessee, have requested waivers and adjustments from CMS to offset this possibility, for now, the responsibility remains at hand. Aducanumab’s (Aduhelm; Biogen) $56,000 price point reflects the larger challenges of the United States’ insurance system and incites a cyclical series of events that have repercussions on cost of future therapies, state budgets, and legislative decisions. Other than that, doctors suggest that people, especially the elderly and those with family history, should keep their brains active and engaged.
Explained: Aducanumab, new drug for Alzheimer’s disease and row over approval
The drugmaker said Monday that it will cut the wholesale acquisition cost of the drug by about 50% next month. Biogen is slashing the price of its Alzheimer’s treatment in half months after it debuted to widespread criticism for an initial cost that could reach $56,000 annually. Sometimes there is no sympathy about the patient not being able to remember anything and their condition is attributed to mental weakness or depression. Once diagnosed after ruling out treatable causes of memory loss, there are usually aducanumab price in india four types of medications, including blood thinners for vascular blockages, and memory enhancing medicines (which do not increase memory power) to increase conduction between neurons. While there is slow but growing recognition that dementia is a major public health problem, doctors say there are low acceptance levels among families. “A lot of time is spent refuting the problem and taking multiple opinions till such time that the patient worsens and then is taken to the neurologist,” said Dr Deshpande.
The statistical review and evaluation of aducanumab by the FDA stated that the available data did not seem to provide sufficient evidence to support the efficacy of high-dose aducanumab amongst individuals with AD.10 The reviewers noted several issues with the trial data regarding aducanumab. (1) Both studies were terminated early for futility and were not fully completed, with the data cut-off date being 26 December 2018 and the public futility announcement date being 21 March 2019. (2) There was sporadic unblinding for dose management of ARIA cases, which was noted to be much higher in the drug-treated group.
Stakeholders include individuals with AD, their families and caregivers, clinicians, healthcare systems, health insurance companies, the pharmaceutical industry and various governmental agencies, amongst others. Additionally, we foresee issues of equity in access to treatment of AD based on lack of knowledge, stigma and cost of treatment, especially amongst minorities and ethnic communities. The annual cost of $50,000 for aducanumab that has been suggested by market analysts would not be commensurate with its clinical benefits.
Statistical review and evaluation of aducanumab by the FDA
Still, trial results are not convincing,” said Dr Manoj Hunnur, Mumbai-based neurologist. Since there is no treatment so far, the drug that can slow down the process holds much promise and is a ray of hope, said Dr Amit Dias, Assistant Professor, Department of Preventive Medicine, Goa Medical College, and a member of Alzheimer’s and Related Society of India. “The drugs we have so far only attempted to improve the function by acting at the level of neurotransmitters,” Dr Dias said.
“The $56,000 price for aducanumab is a rational manufacturer response to an irrational insurance system. If the United States does not wish to face similarly high prices for each new pharmaceutical product, it must address the inflationary incentives inherent in Medicare’s reimbursement formula, the method of drug distribution for https://1investing.in/ infused drugs, and the structure of consumer cost-sharing,” Robinson concluded. Donanemab, on the other hand, is administered once a month and is stopped once patients reach a certain threshold for amyloid levels. The 35% slower cognitive decline is measured using a scale called integrated Alzheimer’s Disease Rating Scale (iADRS).
We derived rates of progression and mortality from the National Alzheimer’s Coordinating Center Uniform Data Set (Table S1 in supporting information). 5
For the cohort receiving aducanumab, we assumed that patients did not transition beyond mild AD. The company expects nearly 900 sites to be ready to administer the drug in the US alone. Experts believe that the drug will reach about eight per cent of Americans with mild Alzheimer’s disease by 2025, minting $7 billion in revenue for Biogen in the process.
Aducanumab is a human IgG1 anti-Aβ monoclonal antibody selective for Aβ aggregates.9 Biogen conducted two identically designed 18-month-long randomized, double-blind, placebo-controlled, parallel-group studies (301 and 302) that evaluated the efficacy, safety and pharmacokinetic and pharmacodynamic properties of aducanumab. The double-blind placebo-controlled period was followed by a dose-blinded long-term extension. The participants were individuals who were between 50 and 85 years of age, had a diagnosis of early symptomatic AD and were positive for brain amyloid pathology as assessed by PET. Inclusion criteria were (1) participants must have had a baseline Mini-Mental State Examination (MMSE) score of 24–30 and (2) a Clinical Dementia Rating-Sum of Boxes (CDR-SB) global score of 0.5. In the studies, individuals who were ApoE ɛ4 carriers and ApoE ɛ4 non-carriers were enrolled. Approximately 80% of participants in both studies had a baseline clinical diagnosis of MCI due to AD and about 20% had a diagnosis of mild AD dementia.